4, 4&#39;-bis-biguanidostilbenedisulfonamides



their salts and processes for preparing same.

United States Patent Ofiice 3,118,937 Patented Jan. 21, 1964 3,118,937-4,4 BIS-BIGUANlDOSTILBENEDlSULFONAMIDES Adrian Marxer, Muttenz,Switzerland, assignor to Cilia Corporation, a corporation of Delaware NoDrawing. Filed June 8, 1960, Ser. No. 34,620 Claims priority,application Switzerland June 16, P359 Claims. ((11.260-556) The presentinvention provides as new products 4- biguanido-diphenyl compounds whichcontain in the 4- position an amino group or a further biguanido groupand in which the benzene nuclei are linked together by a divalent loweraliphatic hydrocarbon radical, as well as of The new compounds may befurther substituted, for example in the phenyl nuclei by lower alkyl oralkoxy groups or halogen atoms, above all by sulfonamido groups or atthe nitrogen atoms, especially the terminal nitrogen atoms of thebiguanido group, for example by lower alkyl or cycloalkyl radicals, suchas methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, penty-l,isopentyl, cyclopentyl, or cyclohexyl groups. The lower divalentaliphatic hydrocarbon radical which links the two benzene nucleicontains advantageously at most 3 carbon atoms and is preferably a loweralkylene radical, for example, amethylene or ethylene radical, or analkenylene radical, such as an ethenylene, alkylidene or alkenylideneradical.

The new compounds have valuable chemotherapeutic properties. Inter alia,they are active against microorganisms and viruses, more especiallyprotozoa, primarily trypanosomas, and are thus intended to be used asmedicaments. Thusthey can be used in infectious diseases caused bytrypanosomas.

Of special value are 4:4'-bis-biguanido-stilbene compounds that aresubstituted by a sulfonamido group in each of the two benzene nuclei,preferably in 2:2 -position, above all the4:4'-bis-biguanido-stilbene-2:2'-disulfonamide of the formula NI-I N11as Well as the salts thereof.

The new compounds are obtained when in an as such known manner in a4-R-diphenyl compound or a salt thereof, in which R represents an aminogroup containing hydrogen, and which contains in the 4-position an aminogroup or a substituent convertible into an amino group and in which thebenzene nuclei are linked by .a lower divalent aliphatic hydrocarbonradical, at least .one of its amino groups containing hydrogen isconverted into a biguanido group, asubstituent in the 4-position whichis convertible into an amino group is so converted and, if desired, aresulting amino group containing hydrogen is converted into a biguanidogroup.

A radical convertible into an amino group is for example one which canbe converted into such a group by hydrolysis or reduction, above all anacylamino, nitro, diazo, azo or azoxy'group. The conversion is performedin per se conventional manner. Amino groups containing hydrogen areprimarily free or monosubstituted, such as mono-lower alkylated, aminogroups.

The conversion of the amino group into a biguanido group is carried out,e.g., in adirect way, advantageously by reacting the free amine or asalt thereof with di cyandiamide or a substituted, for examplealkylated, dicyandiamide.

Thus, a 4:4'-diaminostilbene, in which the two benzene nuclei aresubstituted by a sulfonamido group each, or a mono-salt or bis-saltthereof, can be reacted with dicyandiamide, whereby according to theindividual conditions the monoor bis-guanido compounds or their saltsare obtained.

A preferred embodiment of the indirect conversion of an amino group intoa biguanido group consists in the diazotization of the amino group,coupling of the diazonium salt with dicyandiamide, .e.g.,,in aqueous,alkali carbonate solution, decomposing the coupling product, e.-g.,with gaseous hydrochloric acid and treatment with hot water, andadditive combination of ammonia or primary or secondary amines with thecyanguanido group so formed.

The reactions are performed in the known manner in the presence orabsence of diluents and/or condensing agents and/or catalysts, at theordinary or a raised temperature, under atmospheric or superatmosphericpressure.

It is of advantage to perform the reactions in solution, for example inwater or an alcohol, such as methanol, ethanol, propanol, isopropanol, abutanol, an amyl alcohol, ethylene glycol or a lower alkyl ether ormixtures thereof, or .in a Weak organic base such as pyridine ordimethylaniline.

When dicyandiamide is used, a useful condensing agent is an acid, moreespecially a strong inorganic acid, such as hydrochloric acid orcomplex-forming metal salts, e.g., copper-H-salts. When the solvent usedis a weak organic base, it is of advantage to use as condensing agent asalt of such compound with a strong acid, for example pyridinehydrochloride or dimethylaniline hydrochloride. Resulting complexes canbe split up in the usual manner, copper complexes, for example by meansof hydrogen sulfide in acid solution.

The bis-biguanido compounds are advantageously prepared from bis-saltsof the diamino compounds by reacting such a salt with 2 or moremolecular proportions of dicyandiamide, The mono-biguanido compounds arepreferably prepared from mono-salts of the diamino compounds by reactionwith the calculated proportion of dicyandiamide; when the reactionproduct is then further reacted with a dicyandiamide, the bis-biguanidoderivative is obtained.

Nitrogen atoms capable of substitution, present .in the resultingcompounds, can be further substituted in the conventional manner, forexample they may be loweralky'lated.

The invention further includes any modification of the present processin which an intermediate obtained at any stage of the process is used asstarting material and the remainingstep or steps are carried out, or theprocess is discontinued at any stage thereof.

According to the reaction conditions employed the new compounds areobtained in the form of the free bases or or the salts thereof. From thesalts of the free bases the bases can be obtained :in the known manner,and free bases can be converted into salts by known methods.Therapeutically useful salts can be formed with inorganic acids, such asthe hydrohalic acids, sulfuric acids, nitric acid, phosphoric acids,thiocyanic acid, or organic acids such, for example, as acetic acid,propionic acid, oxalic, malonic, succinic, tartaric, malic acid,methanesulfonic acid, ethanesulfonic acid, hydroxy-ethanesulfonic acid,benzenesulfonic or toluenesulfonic acid, or therapeutically usefulacids.

The starting materials are known or can be made by known processes, ifdesired in the course of the reaction. Preferred starting materials arethose which yield the compounds specifically mentioned hereinbefore asbeing particularly valuable.

The new compounds can be used as medicaments, for is filtered off thehot reaction mixture, and the filtrate example in the form ofpharmaceutical preparations conis treated with alcohol and reduced to asmall volume taining them or their salts in admixture with apharmaceuunder diminished pressure. The resulting solid substance ticalorganic or inorganic excipient suitable for cnteral of is suctioned offand washed with alcohol. parenteral administration. Such excipients canbe made 5 The resulting 4-amino-4'-biguanido-stilbene hydrochlofromsubstances that do not react with the new comride melts unsharply atabout 300 C.; it corresponds pounds, such as water, gelatine, lactose,starches, magneto the formula sium stearate, talc, vegetable oils,benzyl alcohols, gums,

polyalkylene glycols or other known pharmaceutical ex-OHmEQNILCNEWNHLHCI cipients. The pharmaceutical preparations may be, forI! ll example, tablets or dragees, or in liquid form solutions, NH NHsuspensions or emulsions. They may be sterilized and/ Example 3 or maycontain assistants such as preserving, stabilizing, I I

Wetting or l if i agents, salts f regulating the A mixture of 10.51grams of 4:4-d1aminost1lbenc, 8.6

,. grams of dicyandiamide and 200 cc. of 0.5 N-hydroosmotic pressure, orbutters. They may also contain further therapeutically valuablesubstances' The prepara- 9111011}: acld f tl 1 hours under reflux. Theresulting crystalhzate 15 isolated and boiled with 1.5 liters tions areformulated by the conventional methods.

h f ll i examples illustrate the invention of water. The slightly turbidfiltrate rs filtered, boiled for a short time with a small amount ofactive carbon and Example 1 again filtered. The clear solution isevaporated under A suspension of 18.4 grams of 4:4-diamino ti1b nreduced pressure until crystallization sets in. The re-2:2'-disulfonamide in 75 cc. of water is mixed with 17 cc. Suiting414'-bi$bigllanid0$ti1ben dihydrochloride of m6 of 6.04 N-hydroch1oricacid and then with 8.4 grams of formula dicyandiamide, and the mixtureis refluxed with stirring melts at -177 C- for 7 hours. After thestarting materials have passed Whfltis C a disi into solution, theproduct crystallizes out; it is allowed to 90 A member l t d from thgroup Consisting of a cool, suctioned oil and washed with a small amountof U 4-biguflflido-stilbene Compound Oflhe formula: water. The residueis extracted by being boiled with 200 cc. of alcohol, and the insolublematter is once again S removed. NH NH In this manner the dihydrochlorideof 4:4'-bis-biguani- 502N111 SWNHI dostilbene-2:2'-disulfonamide of theformula wherein R represents a member selected from the group NH NH NENH 802N113 SOgNHz is obtained. It melts at 292 C. with decomposition,consisting of amino and biguanido, and an addition salt gives a clearsolution in water, and can be precipitated thereof with atherapeutically acceptable acid.

in the form of the base with sodium carbonate. 2. A4,4-bis-biguanido-stilbene compound of the for- The4:4-diaminostilbene-2:2'-disulfonamide, used as mula:

starting material, can be prepared by reducing 4:4-di- 3. An additionsalt of a 4,4-bis-biguanido-stilbene comnitrostilbene-Z:2'-disu1fonamidewith zinc dust in alcoholic pound of the formula:

glacial acetic acid. It melts at 274-278 C. The 4,4-withatherapeutically acceptable acid. dinitrostilbene-2,2-disulfonamideis obtained by boiling 4. An addition salt of4,4-bis-biguanido-stilbene-2,2'-di- 4,4'-dinitro-stilbene-2,2-disulfonicacid with phosphorus sulfonamide with a pharmaceutically acceptableacid. oxychloride, pouring the reaction mixture on ice and add- 5.4,4-Bis=biguanido-stilbene-2,2-disulfonamide.

ing a concentrated aqueous solution of ammonia.

References Cited in the file of this patent Example 2 UNITED STATESPATENTS A suspension of 10.51 grams of 4z4'-diaminost be 2,255,090Tinker et a1. Sept. 9, 1941 in cc. of N-hydrochloric acid and 50 cc. fWat r is 2,331,377 DAlelio Oct. 12, 1943 treated with 4.2 grams ofdicyandiamide. The mixtu e i 2,901,477 Siegel et a]. Aug. 25, 1959heated with stirring for 4 hours on an oil bath at C. The resulting,thick magma is extracted by being boiled OTHER REFERENCES with 700 cc.of water, a small amount of insoluble matter Rey et al.: C.A., vol. 45,page 8487 (1951).

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A 4-BIGUANIDO-STILBENECOMPOUND OF THE FORMULA: